The use of mathematical models to design sleep-wake and countermeasure schedules for improved performance is proposed. Travel across multiple time zones results in desynchronization of environmental time cues and the sleep-wake schedule from their normal phase relationships with the endogenous circadian system. Circadian misalignment can result in poor neurobehavioral performance, decreased sleep efficiency, and inappropriately timed physiological signals including gastrointestinal activity and hormone release. Frequent and repeated transmeridian travel is associated with long-term cognitive deficits, and rodents experimentally exposed to repeated schedule shifts have increased death rates. One approach to reduce the short-term circadian, sleep-wake, and performance problems is to use mathematical models of the circadian pacemaker to design countermeasures that rapidly shift the circadian pacemaker to align with the new schedule. The approach includes "cutting-edge" mathematical and computer science methods for designing interventions that combine an algorithm for optimal placement of countermeasures with a novel mode of schedule representation. Our preliminary results demonstrate that rapid circadian resynchrony and the resulting improvement in neurobehavioral performance can be quickly achieved even after moderate to large shifts in the sleep-wake schedule. The key schedule design inputs are endogenous circadian period length, desired sleep-wake schedule, length of intervention, background light level, and countermeasure strength. A new schedule representation is proposed as a mechanism that facilitates schedule design, simulation studies, and experiment design to significantly decrease the amount of time to design an appropriate intervention. The proposed methods have direct implications for designing jet lag, shift-work, and non-24-hour schedules, including scheduling for extreme environments, such as in space, undersea, or in polar-regions. The proposed research meets several objectives of the National Institute of General Medical Sciences including the use of bioinformatics and computational biology to determine interventions that alleviate the effects of jetlag and shift-work on multiple-organ systems including behavior. The proposed training aims to integrate mathematical, computational, and circadian/sleep research methods into a common framework and meets the aim of NIGMS to train well-prepared scientists at the interface of different fields. PUBLIC HEALTH RELEVANCE: This work could affect the millions of people yearly who must work and sleep at time at which their circadian system is promoting the opposite behavior: this includes people experiencing jet lag or who must work night or rotating shifts. This desynchrony between internal circadian clock time and external environmental time affects 5 billion passengers who travel by air yearly, and 20% of global industrial employees who are shift workers, including 4.5 million international transport workers, and 1.4 million US military personnel who are often expected to work optimally despite changes in their schedule. The ultimate goal of this research is to make a set of mathematical, computational, and software tools that allow knowledge derived from circadian and sleep research to be used by non-professionals.